Use of testosterone and a 5-HT1A agonist in the treatment of sexual dysfunction

ABSTRACT

The invention relates to the field of male and/or female sexual dysfunction. The invention specifically relates to the use of testosterone and a 5-HT1A agonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/513,358, having an international filing date of 2 Nov. 2007, which isa U.S. National Phase of PCT/NL2007/050533 having an internationalfiling date of 2 Nov. 2007, which claims benefit of European patentapplication No. 06076976.7 filed 3 Nov. 2006. U.S. patent applicationSer. No. 13/545,916, filed 10 Jul. 2012 is also a continuation of U.S.patent application Ser. No. 12/513,358. The contents of the above patentapplications are incorporated by reference herein in their entirety.

BACKGROUND OF THE INVENTION

The invention relates to the field of male and/or female sexualdysfunction. The invention specifically relates to the use oftestosterone and a 5-HT1A agonist, optionally in combination with a PDE5inhibitor.

Male Sexual Dysfunction (MSD) refers to various disturbances orimpairments of male sexual function, including inhibited sexual desire(ISD), erectile dysfunction (ED) or impotence and premature ejaculation(PE, also known as rapid ejaculation, early ejaculation, or ejaculatiopraecox) and anorgasmia. ED is treated successfully using PDE5inhibitors such as sildenafil, vardenafil and tadalafil. Currentsuccessful treatment for PE includes anesthetic creams (like lidocaine,prilocaine and combinations) that reduce sensation on the penis and SSRIantidepressants such as paroxetine, fluoxetine and sertraline. There iscurrently no known successful medication for ISD.

Female Sexual Dysfunction (FSD) refers to various disturbances orimpairments of sexual function, including a lack of interest in sexualactivity, repeated failure to attain or maintain sexual excitement,inability to attain an orgasm following sufficient arousal. A recentstudy estimated that 43% of women suffer from sexual dysfunction in theUSA[1]. Low sexual desire (22% prevalence) and sexual arousal problems(14% prevalence) belong to the most common categories of sexualdysfunction of women. These categories are convenient in providingworking definitions and an accepted lexicon for researchers andtherapists. However, it may be incorrect to assume that these disordersare fully independent of each other. Both case studies andepidemiological studies demonstrate that these disorders can overlap andmay be interdependent. In some cases, it may be possible to identify theprimary disorder that led to the others, but in many cases, this may beimpossible.

For the treatment of male and/or female sexual disorder (or dysfunction)a number of different treatments, with greater or lesser degrees ofsuccess have been suggested and applied. For example, WO 2005/107810describes the use of testosterone and a type 5 phosphodiesterase (PDE5)inhibitor which components must be released within a certain order andtimeframe in respect of sexual activity. Although this treatmentprovides promising results, there is a need for alternative treatments.

In one of its embodiments, the invention provides use of testosteroneand a 5-HT1A agonist in the preparation of a medicament for thetreatment of sexual dysfunction, wherein said 5-HT1A is essentiallyreleased one hour before and said testosterone 3.5-5.5 hours prior tosexual activity. In a preferred embodiment said testosterone issublingual testosterone.

Testosterone is also known under the chemical name17-β-hydroxyandrost-4-en-3-one which can be obtained in various ways: itmay be isolated and purified from nature or synthetically produced byany manner. Besides testosterone also an “analogue of testosterone” canbe used. The term “or analogue thereof” includes any useful metaboliteor precursor of testosterone, for example the metabolitedihydrotestosterone. It is clear to the skilled person that if ametabolite or precursor of testosterone is used, the time point foradministration of for example a 5-HT1A agonist (and optionally also aPDE5 inhibitor) needs to be reconsidered. If, for example,dihydrotestosterone is used, the time of administration of a 5-HT1Aagonist lies approximately half an hour earlier (as this is theapproximate time it takes for excess testosterone to be converted todihydrotestosterone).

According to the invention the level of free testosterone should be apeak plasma level of free testosterone of about at least 0,010 nmol/L,which will typically occur between 1 and 20 minutes after administrationof the testosterone. About three and a half to five and a half hoursafter this plasma testosterone peak, there is a testosterone effectpeak, i.e., there is a time lag in the effect of testosterone on genitalarousal in sexually functional women.

Testosterone is preferably given in a formulation wherein there is ashort-lasting high peak of testosterone in the blood circulation of thesubject to whom it is administered. The invention therefore provides ause, wherein the testosterone or an analogue thereof is provided in theform of a sublingual formulation, such as a sublingual formulationcomprising cyclodextrins as carrier. Another example of a suitable routeof administration is buco-mucosally or intranasally, which can also beperformed with the use of a cyclodextrin formulation or other usualexcipients, diluents and the like. A typical example of a formulation isgiven in hydroxypropyl-beta cyclodextrin, but other beta cyclodextrinsand other usual excipients, diluents and the like are within the skillof the art for preparing a formulation comprising testosterone or ananalogue thereof, which releases essentially all of the testosteronewithin one short burst. Said burst will typically be within a short timeinterval (for example within 60-120 seconds, more preferably within 60seconds) upon administration, leading to blood peak levels oftestosterone about 1-20 minutes later. In a preferred embodiment, thepharmaceutical is designed for sublingual administration and even morepreferred said composition comprises cyclodextrin such ashydroxypropyl-beta cyclodextrin. A typical example of a preparedtestosterone sample (for 0.5 mg of testosterone) consists of 0.5 mgtestosterone, 5 mg hydroxypropyl-betacyclodextrines (carrier), 5 mgethanol, and 5 ml water, but each of the amounts of these substancesmight be higher or lower.

Testosterone in the circulation is typically bound by SHBG (steroidhormone binding globulin) and by albumin. It is important that the peakplasma level of testosterone as defined in the present invention ispresent and calculated as free testosterone, so a fraction not bound byalbumin and SHBG. Thus the dose of testosterone given should be highenough to saturate the albumin and SHBG (i.e., the concentration oftestosterone must be high enough to overcome complete binding oftestosterone by SHBG or albumin), or another way of avoiding binding toalbumin or SHBG must be designed, such as the use of a competitor forthe testosterone binding site on SHBG.

In contrast to other sexual dysfunction treatments based ontestosterone, the use (and method) described herein aim at a temporaryincrease in the testosterone level in the treated subject. Most othermethods aim at restoring/replacing/replenishing of the testosteronelevel to normal (i.e., physiological) levels (as found in a normalsubject). In a preferred embodiment, testosterone is applied such that ashort-lasting high peak of testosterone in the blood circulation of thesubject to whom it is administered, is obtained. The term“short-lasting” refers to an application of testosterone such that theblood serum testosterone levels are back to base-line level within 2hours after administration.

Preferably, the used 5-HT1A agonist is selective for the 5-HT1A receptorover other 5-HT receptors and the α-adrenoreceptor and dopaminereceptor. Non-limiting examples of a 5-HT1A agonist are 8-OH-DPAT,Alnespirone, AP-521, Buspar, Buspirone, Dippropyl-5-CT, DU-125530,E6265, Ebalzotan, Eptapirone, Flesinoxan, Flibanserin, Gepirone,Ipsapirone, Lesopitron, LY293284, LY301317, MKC242, R(+)-UH-301,Repinotan, SR57746A, Sunepitron, SUN-N4057, Tandosporine, U-92016A,Urapidil, VML-670, Zalospirone or Zaprasidone.

The application of a 5-HT1A agonist is such that, just as thetestosterone, there is a peak present within the blood. In a preferredembodiment, the used 5-HT1A agonist is applied such that there is a peakwithin the blood around 4 hours after the (burst release) administrationof testosterone.

The application of testosterone as well as a 5-HT1A agonist is acute,i.e., on demand, and not chronic. In other words, the administration oftestosterone and/or a 5-HT1A agonist is only done just before sexualactivity, compared to a chronic dosing regime/situation/application thataims at restoring the levels to physiological levels.

Reference herein to sexual dysfunction includes male and/or femaledysfunction. Reference to male sexual dysfunction includes inhibitedsexual desire (ISD), erectile dysfunction (ED) and premature ejaculation(PE).

Reference to female sexual dysfunction includes Hypoactive Sexual DesireDisorder (HSDD), Female Sexual Arousal Disorder (FSAD) and FemaleOrgasmic Disorder (FOD).

Without being bound by it, the inventors provide the followingexplanation for the treatment of sexual dysfunction by providing asubject in need thereof with testosterone and a 5-HT1A agonist.Testosterone makes the brain more receptive for sexual cues andincreases subjective sexual arousal. To prevent humans from acting uponsuch arousal in situations where this is deemed inappropriate, theprefrontal cortex can inhibit automated/reflexive responses, therebyalso inhibiting physical sexual arousal. We pose that women with FSD, inparticular women with FSAD, suffer from exaggerated inhibitory action ofthe prefrontal cortex, which is relieved (inhibition-of-inhibition) byusing a 5-HT1A agonist.

The embodiments referring to a 5-HT1A agonist are preferably used totreat female sexual dysfunction, i.e., to improve subjective andphysical sexual arousal (female sexual arousal disorder) and isespecially effective in women suffering from female sexual arousaldisorder, by disinhibiting the brain's inhibition of sexual behaviour.

In a preferred embodiment, the invention provides use of testosteroneand a 5-HT1A agonist in the preparation of a medicament for thetreatment of female sexual dysfunction, wherein said 5-HT1A isessentially released one hour before and said testosterone 3.5-5.5 hoursprior to sexual activity. In yet another preferred embodiment, theinvention provides use of testosterone, a PDE5 inhibitor and a HT1Aagonist in the preparation of a medicament for the treatment of femalesexual dysfunction, wherein said 5-HT1A is essentially released one hourbefore, said PDE5 inhibitor 1-2 hours and said testosterone 3.5-5.5hours prior to sexual activity. Preferably said female sexualdysfunction is female sexual arousal disorder (FSAD).

In yet another preferred embodiment, said sexual dysfunction is malesexual dysfunction.

It is clear, that preferably the (peak) effect of a 5-HT1A agonist aswell as the (peak) effect of testosterone coincide (completely). It ishowever noted that if the peak effect of testosterone and of a 5-HT1Aagonist only partly overlap this still results in the desired effect.When the testosterone is provided such that it essentially releases allof the testosterone within one short burst to a (for example female)subject, a 5-HT1A agonist is preferably provided such that it results ina peak plasma concentration at least 3 hours after the administration oftestosterone. Even more preferred, the 5-HT1A agonist effect is present3.5-5.5 hours after the intake of testosterone. It is clear that theexact time of the 5-HT1A agonist administration is dependent on the typeof formulation used. If the 5-HT1A agonist formulation is releasedshortly after administration, it is of no use to provide it at the sametime as the testosterone is provided, because there will be hardly anyoverlap of effect. If it takes some time before the 5-HT1A agonist isavailable from the used formulation, for example 3.5 to 4.5 hours, itcan be/is administrated at the same time the testosterone isadministered.

Without being bound by theory, the experimental part herein describesthe inventor's current hypothesis in respect of the effect of a 5-HT1Aagonist in the treatment of sexual dysfunction.

In yet another embodiment, the invention provides use of testosterone, aPDE5 inhibitor and a 5-HT1A agonist in the preparation of a medicamentfor the treatment of sexual dysfunction, wherein said 5-HT1A isessentially released one hour, said PDE5 inhibitor 1-2 hours and saidtestosterone 3.5-5.5 hours prior to sexual activity. In a preferredembodiment said testosterone is sublingual testosterone.

Multiple PDE5 inhibitors are available. An example of a PDE5 inhibitoris vardenafil HCl which is designated chemically as piperazine,1-[[3-(1,4-dihydro-5-methyl-4-oxo-7-propylimidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxyphenyl]sulfonyl]-4-ethyl-,monohydrochloride. In addition to the active ingredient, vardenafil HCl,each tablet contains microcrystalline cellulose, crospovidone, colloidalsilicon dioxide, magnesium stearate, hypromellose, polyethylene glycol,titanium dioxide, yellow ferric oxide, and red ferric oxide. Anotherexample is given in sildenafil citrate which is chemically designated as1-[[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1Hpyrazolo[4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulfonyl]-4-methylpiperazinecitrate. In addition to the active ingredient, sildenafil citrate, eachtablet contains the following ingredients: microcrystalline cellulose,anhydrous dibasic calcium phosphate, croscarmellose sodium, magnesiumstearate, hydroxypropyl methylcellulose, titanium dioxide, lactose,triacetin, and FD & C Blue #2 aluminum lake. Another example is given intadalafil which is chemically designated aspyrazino[1′,2′:1,6]pyrido[3,4-b]indole-1,4-dione,6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-, (6R,12aR)-.In addition to the active ingredient, tadalafil, each tablet containsthe following ingredients: croscarmellose sodium, hydroxypropylcellulose, hypromellose, iron oxide, lactose monohydrate, magnesiumstearate, microcrystalline cellulose, sodium lauryl sulfate, talc,titanium dioxide, and triacetin.

The number of PDE5-inhibitors is still expanding and other non-limitingexamples are: E-4021, E-8010, E-4010, AWD-12-217 (zaprinast), AWD12-210, UK-343,664, UK-369003, UK-357903, BMS-341400, BMS-223131,FR226807, FR-229934, EMR-6203, Sch-51866, IC485, TA-1790, DA-8159,NCX-911 or KS-505a or the compounds disclosed in WO 96/26940.

It is clear to the skilled person that the active ingredients arepreferably administrated/released such that their peak effects (i.e.,their activities) at least partly overlap/coincide and preferablycompletely overlap. In respect of testosterone the peak effect means themaximal increase in attention to erotic stimuli and in sexualmotivation. For a PDE5 inhibitor the peak effect is the maximal increasein activity of the NANC (non adrenergic non cholinergic) pathway of theautonomous nervous system and in respect of a 5-HT1A agonist this meansa maximal behavioural disinhibition. This goal can be reached by usingdifferent strategies.

As outlined above, for an optimal effect of testosterone, a 5-HT1Aagonist and a PDE5 inhibitor, it is desired that the peak effect of saidcompounds coincide. However, even if the peak effects only overlappartly, this still results in the desired effect (for example, treatmentof FSD). There is a time lag for the effect of a 5-HT1A agonist of about1 hour and the effect of a 5-HT1A agonist lasts for several hours (forexample, flesinoxan reaches maximum plasma concentration after 1-2hours, and single doses have a half-life of 5.5 hours). PDE5-inhibitorssuch as vardenafil and sildenafil typically reach their peak plasmaconcentration (which should be at least 35 ng/ml for sildenafil, 2 μg/lfor vardenafil and 40 μgl for tadalafil) after about 1 hour afteradministration and their effect is then also present. By releasing a5-HT1A agonist and a PDE5 inhibitor at approximately the same time,their effects at least partly coincide. It is clear to the skilledperson that a 5-HT1A agonist and a PDE5 inhibitor can be formulated suchthat their release is delayed. For example, the active ingredients areprovided with or surrounded by a coating, which is dissolved after 2hours. In such a case, the active ingredients must be taken 1.5-3.5hours before sexual activity. Other variations are easily performed bythe skilled person and are within the scope of the present invention.

For the present invention the routes of administration of choice arethose which are the least invasive (for example oral, buco-mucosal orintranasal). Motivation for sexual behaviour should not be negativelyinfluenced by invasive routes of administration.

The use as described herein may alternatively be formulated as:

-   -   (i) testosterone and a 5-HT1A agonist for use in a method for        treating sexual dysfunction; or    -   (ii) testosterone, a PDE5-inhibitor and a 5-HT1A agonist for use        in a method for treating sexual dysfunction.

The invention further provides a pharmaceutical composition comprisingtestosterone and a 5-HT1A agonist, wherein said formulation is designedto essentially release said 5-HT1A one hour and said testosterone3.5-5.5 hours prior to sexual activity.

The amount of testosterone per pharmaceutical composition comprisingtestosterone is at least 0.3 mg testosterone and at most 2.5 mgtestosterone. Higher or lower doses may be necessary depending on thealbumin and SHBG levels and the weight of the subject to be treated.

The suitable amount of 5-HT1A agonist depends on the used 5-HT1A agonistas well as on for example the weight of the patient. Flesinoxan forexample is typically provided in an amount of 1 mg.

The invention also provides a pharmaceutical composition comprisingtestosterone, a PDE5 inhibitor and a 5-HT1A agonist, wherein saidformulation is designed to essentially release said 5-HT1A one hour,said PDE5 inhibitor 1-2 hours and said testosterone 3.5-5.5 hours priorto sexual activity. One suitable amount of a 5-HT1A agonist isapproximately 1 mg. An advantage of using at least three differentactive ingredients is that the individual used amounts may be decreasedif compared to a treatment based on two active ingredients.

The active ingredients (for example testosterone, a PDE5 inhibitor or a5-HT1A agonist) may be present in any suitable form, such as in the formof tablets, capsules, multi-particulates, gels, films, solutions orsuspensions and may comprise diluents and/or excipients and/or bindersand/or disintegrants and/or lubricants and/or coloring agents. Alsodifferent kinds of release patterns can be applied, such as directrelease or delayed release.

Because the effects of the different active ingredients must at leastpartly coincide and preferably completely coincide, the inventionpreferably also provides instructions as to the administration.Therefore, the invention also provides a kit of parts comprising atleast one pharmaceutical composition comprising testosterone and atleast one composition comprising a 5-HT1A agonist, wherein said kitfurther comprises instructions in respect to the administration of saidcompositions. In yet another embodiment, the invention also provides akit of parts comprising at least one pharmaceutical compositioncomprising testosterone, at least one composition comprising a PDE5inhibitor and at least one composition comprising a 5-HT1A agonist,wherein said kit further comprises instructions in respect to theadministration of said compositions.

It should be clear that depending on the formulation of the differentactive ingredients, different administration regimes can be used.

In order to further enhance the effects of the kit of parts of theinvention said kit may further comprise means for cognitiveinterventions and stimulation. Such information may be present on anydata carrier (paper, CD, DVD), passive or interactive, or it may be alink to a website at least partially designed for the purpose of saidcognitive stimulation. Sometimes it is preferred to present saidcognitive stimulatory information subconsciously, e.g., subliminally.

The herein described combinations of active ingredients may further beaccompanied by other suitable active ingredients.

The invention further provides a method for treating a male or a femalesuffering from sexual dysfunction by providing to said male or femalewith a combination of testosterone and a 5-HT1A agonist (and optionallya PDE5-inhibitor).

The invention will be explained in more detail in the following,non-limiting examples.

EXPERIMENTAL PART

Case reports on combined Testosterone and Buspirone medication for FSD

Rationale

A number of women who had participated in our FSD-medication trials hadreported strong feelings of inhibition whilst contemplating or havingsexual intercourse. Three of these women were prescribed a single doseof testosterone (T) combined with a single dose of Buspirone (B), by aqualified physician, in a laboratory setting. T is known to make thebrain more perceptive to sexual stimuli, B was given for its 5-HT1Areceptor agonism, to reduce said inhibition.

Set-Up

All women were given Placebo or T/B medication randomly and on separatedays. T (0.5 mg, suspension, sublingually) was given 4 hours and B (5mg, tablet, orally) was given 1.5 hours prior to measurements. Physicalarousal was measured using Clitoral Blood Volume (CBV) measurements;subjective sexual arousal was measured using the Sexual Arousal ResponseSelf-Assessment Questionnaire (SARSAQ). In addition, Vaginal PulseAmplitude (VPA) was measured as a measure for physical anticipation ofsexual activity. CBV and VPA were measured during neutral filmclips, andsubsequent erotic filmclips. Each session of neutral and eroticfilmclips was followed by a SARSAQ. The erotic film clips wereprogressively more explicit during subsequent (total of four) sessions.The results below are described as the overall relative increase inphysical arousal (CBV and VPA, in percent points) and subjective sexualarousal (SARSAQ, in Likert scale points) during the erotic filmclipsunder placebo and T/B condition.

Case A

This woman was diagnosed with both Hypo Sexual Desire Disorder (HSDD,DSM-IV TR inclusion criteria) and Female Sexual Arousal Disorder (FSAD,DSM-IV TR inclusion criteria). She feels sexually inhibited, which isonly released when she's had too much to drink. She interpretscompliments about her looks as direct invitation for sex whichimmediately results in feelings of inhibition.

Average SARSAQ increase was 0.44 points, peaking at 0.9 points duringthe third session neutral/erotic film clips. Average increase in VPA was1.3 points, peaking at 3.9 during the second session. Average increasein CBV was 10.2 peaking at 12.6 during the third session.

Case B

This woman was also diagnosed with both HSDD and FSAD. She says she'slost the desire for sex she used to have and finds it very difficult tounwind and is very easily distracted, causing her not to becomephysically aroused.

Average SARSAQ increase was 2.03 points, peaking at 6.23 points duringthe second session neutral/erotic film clips. Average increase in VPAwas -0.4 points, peaking at -0.0 during the first session. Averageincrease in CBV was 4.0 peaking at 5.8 during the first session.

Case C

Case C suffers from HSDD but not from FSAD. She puts much effort intotrying to regain desire for sex, but is often put-off by her partner whoshe claims is overly clingy. Average SARSAQ increase was −0.44 points,peaking at 0.01 points during the first session neutral/erotic filmclips. She did report to the physician that she felt more sexuallyaroused during verum. Average increase in VPA was 0.3 points, peaking at0.3 during the first session. Average increase in CBV was 17.5 peakingat 19.3 during the first session.

Overall Conclusion

Combined treatment with T/B increased physical sexual arousal (CBV) overplacebo, in all three cases. Physical anticipation of sexual activity(VPA) was increased in two out of three cases. Together, thesemeasurements indicate a major improvement in physical sexual arousal.CBV was increased in both FSAD patients, VPA in one out of two.

Subjective sexual arousal, measured by SARSAQ, was increased in two outof three cases, both combined HSDD and FSAD patients. Although theSARSAQ scores of case C did not increase, she did report feeling moresexually aroused during verum.

We expect to further improve these results by using full as opposed topartial 5-HT1A receptor agonists (flesinoxan instead of buspirone), byvarying the dose of 5-HT1A receptor agonist and by combining T/Btreatment with PDE5 inhibitors.

Experiment 1 Testosterone and Flesinoxan in FSD

Efficacy of combined administration of testosterone and a 5-HT1Areceptor agonist—flesinoxan—on VPA in response to erotic film excerptsin women with FSD

In a double-blind, randomly assigned placebo controlled cross-overdesign, a group of 16 women with female sexual dysfunction (FSD) willreceive

-   -   1. testosterone (0.5 mg) and flesinoxan (1 mg)    -   2. testosterone (0.5 mg) alone    -   3. flesinoxan (1 mg) alone    -   4. placebo        on 4 separate experimental days.

The four experimental days will be separated by (at least) a three-dayperiod. On all drug administrations, subjects will receive one capsuleconsisting of either flesinoxan, or a placebo, and one liquidformulation with either testosterone or placebo. The vaginal pulseamplitude will be measured in response to neutral and erotic filmexcerpts, directly after administration of liquid formulation, and 4hours after administration of liquid formulation. Thus, the liquidformulation will be taken four hours prior to testing, the capsule onehour prior to testing. The effect of sublingual testosterone andflesinoxan will overlap due to their different time lag (3.5-4.5 hoursand 0-1 hour, respectively).

Experiment 2 Testosterone, Flesinoxan and Sildenafil in FSD

Efficacy of combined administration of testosterone, a 5-HT1A receptoragonist—flesinoxan—and PDE5 inhibitor—sildenafil—on VPA in response toerotic film excerpts in women with FSD

In a double-blind, randomly assigned placebo controlled cross-overdesign, a group of 16 women with female sexual dysfunction (FSD) willreceive

-   -   1. testosterone (0.5 mg), flesinoxan (1 mg) and sildenafil (10        mg)    -   2. testosterone (0.5 mg) and flesinoxan (1 mg)    -   3. flesinoxan (1 mg) and sildenafil (10 mg)    -   4. testosterone (0.5 mg) alone    -   5. flesinoxan (1 mg) alone    -   6. placebo        on 6 separate experimental days.

The six experimental days will be separated by (at least) a three-dayperiod. On all drug administrations, subjects will receive one capsuleconsisting of either flesinoxan and/or sildenafil or a placebo, and oneliquid formulation with either testosterone or placebo. The vaginalpulse amplitude will be measured in response to neutral and erotic filmexcerpts, directly after administration of liquid formulation, and 4hours after administration of liquid formulation. Thus, the liquidformulation will be taken four hours prior to testing, the capsule onehour prior to testing. The effect of sublingual testosterone, flesinoxanand sildenafil, will overlap due to their different time lags (3.5-4.5hours, 0-1 hour and 0-1 hour, respectively).

During the experimental sessions of experiments 1-2, the subject mustinsert a tampon-shaped vaginal probe (a photoplethysmograph) in order tomeasure the VPA. Then subjects will view a 10 minute neutral fragment,followed by a 5 minute erotic film fragment. After these baselinemeasurements, the subjects receive one of the four medicationcombinations as described above. Following medication another set ofneutral (5 minutes) and erotic (5 minutes) film fragments is shown. Thevaginal probe will then be removed. After 4 hours another VPAmeasurement will be made in response to neutral (5 minutes) and erotic(5 minutes) film fragments. Blood pressure (supine and standing), heartrate, respiration rate, and body temperature will be monitoredthroughout on the experimental days.

The experimental session will be preceded by a screening visit. In thisscreening visit subjects are interviewed and examined by a resident ofthe department of gynecology of Flevo Hospital, Almere to diagnose forFSD and to determine eligibility for study participation. Subjects willbe asked to fill out a questionnaire; the Female Sexual Function Index(FSFI). Subjects will be screened to exclude pregnancy or breastfeeding, vaginal infections, major operations to the vagina and/orvulva, undetected major gynecological illnesses or unexplainedgynecological complaints. Weight, height, blood pressure (supine andstanding) will be measured. Cardiovascular condition will be tested andECG checked for significant abnormalities.

Subjects with a history of endocrinological, neurological or psychiatricillness and/or treatment. Standard blood chemistry and hematology testswill be performed. Participants are required not to use alcohol orpsychoactive drugs the evening before and the day of experimentation.During period of menstruation, subjects will not be tested.

Experiment 3 Testosterone and Flesinoxan in MSD

Efficacy of combined administration of testosterone and a 5-HT1Areceptor agonist—flesinoxan—on male sexual function in response toerotic film excerpts in men with MSD.

In a double-blind, randomly assigned placebo controlled cross-overdesign, a group of 16 men with male sexual dysfunction (MSD) willreceive

-   -   1. testosterone (0.5 mg) and flesinoxan (1 mg)    -   2. testosterone (0.5 mg) alone    -   3. flesinoxan (1 mg) alone    -   4. placebo        on 4 separate experimental days.

The penile tumescence and rigidity will be measured in response toneutral and erotic film audiovisual stimulation (VSTR), directly afterdrug administration, and 1 hour after drug administration, directlyfollowed by measurement of vibrotactile stimulation ejaculatory latencytime (VTS-ELT) and postejaculatory erectile refractory time. The fourexperimental days will be separated by (at least) a three-day period. Onall drug administrations, subjects will receive one capsule consistingof either flesinoxan, or a placebo, and one liquid formulation witheither testosterone or placebo. The VSTR will be measured in response toneutral and erotic film excerpts, directly after administration ofliquid formulation, and 4 hours after administration of liquidformulation, when also the VTS-ELT is measured. Thus, the liquidformulation will be taken four hours prior to testing, the capsule onehour prior to testing. The effect of sublingual testosterone andflesinoxan will overlap due to their different time lag (3.5-4.5 hoursand 0-1 hour, respectively).

Experiment 4 Testosterone, Flesinoxan and Sildenafil in MSD

Efficacy of combined administration of testosterone, a 5-HT1A receptoragonist—flesinoxan—and PDE5 inhibitor—sildenafil—on male sexual functionin response to erotic film excerpts in men with MSD

In a double-blind, randomly assigned placebo controlled cross-overdesign, a group of 16 men with male sexual dysfunction (MSD) willreceive

-   -   1. testosterone (0.5 mg), flesinoxan (1 mg) and sildenafil (10        mg)    -   2. testosterone (0.5 mg) and flesinoxan (1 mg)    -   3. flesinoxan (1 mg) and sildenafil (10 mg)    -   4. testosterone (0.5 mg) alone    -   5. flesinoxan (1 mg) alone    -   6. placebo        on 6 separate experimental days.

The penile tumescence and rigidity will be measured in response toneutral and erotic film audiovisual stimulation (VSTR), directly afterdrug administration, and 1 hour after drug administration, directlyfollowed by measurement of vibrotactile stimulation ejaculatory latencytime (VTS-ELT) and postejaculatory erectile refractory time. The sixexperimental days will be separated by (at least) a three-day period. Onall drug administrations, subjects will receive one capsule consistingof either flesinoxan, or a placebo, and one liquid formulation witheither testosterone or placebo. The VSTR will be measured in response toneutral and erotic film excerpts, directly after administration ofliquid formulation, and 4 hours after administration of liquidformulation, when also the VTS-ELT is measured. Thus, the liquidformulation will be taken four hours prior to testing, the capsule onehour prior to testing. The effect of sublingual testosterone, flesinoxanand sildenafil, will overlap due to their different time lags (3.5-4.5hours, 0-1 hour and 0-1 hour, respectively).

Experiments 3-4 will be preceded by a screening visit. In this screeningvisit subjects are interviewed and examined by a resident of thedepartment of gynecology of Flevo Hospital, Almere to diagnose for MSDand to determine eligibility for study participation. Subjects will beasked to fill out a questionnaire; the international index of erectilefunction questionnaire (IIEF). Weight, height, blood pressure (supineand standing) will be measured. Cardiovascular condition will be testedand ECG checked for significant abnormalities. Participants are requirednot to use alcohol or psychoactive drugs the evening before and the dayof experimentation.

REFERENCES

1. Laumann, E. O., A. Paik, and R. C. Rosen, Sexual dysfunction in theUnited States: prevalence and predictors. Jama, 1999. 281(6): p. 537-44.

2. Wudy, S. A., et al., Androgen metabolism assessment by routine gaschromatography/mass spectrometry profiling of plasma steroids: Part 1,Unconjugated steroids. Steroids, 1992. 57(7): p. 319-24.

The invention claimed is:
 1. A pharmaceutical composition designed foracute administration in anticipation of sexual activity comprisingtestosterone and a 5-HT1A agonist, wherein said testosterone isformulated for sublingual, buccal-mucosal, or intranasal administrationwith a cyclodextrin to release the testosterone within 120 seconds afteradministration with peak levels of testosterone reached after about 1-20minutes and the 5-HT1A agonist is formulated for delayed release suchthat 5-HT1A is released 2.5 to 4.5 hours after the release oftestosterone.
 2. The pharmaceutical composition of claim 1 which furtherincludes a PDE5 inhibitor, wherein said composition is formulated fordelayed release of said PDE5 inhibitor 1.5-4.5 hours after the releaseof testosterone.
 3. A kit comprising at least one pharmaceuticalcomposition comprising testosterone formulated for sublingual orintranasal administration in a cyclodextrin to release said testosteronewithin 120 seconds after administration with peak levels of testosteronereached after about 1-20 minutes and at least one pharmaceuticalcomposition comprising a 5-HT1A agonist, wherein said kit furthercomprises instructions to administer said compositions acutely inanticipation of sexual activity at a time so that testosterone isreleased 3.5-5 hours prior to sexual activity and 5-HT1A agonist isreleased 1 hour prior to sexual activity.
 4. The kit of claim 3 furthercomprising at least one pharmaceutical composition comprising a PDE5inhibitor along with instructions to administer said PDE5 inhibitor at atime so that it is released 1-2 hours prior to sexual activity.
 5. Thekit of claim 3, wherein the 5-HT1A agonist is buspirone.
 6. The kit ofclaim 3, wherein the testosterone composition comprises between 0.3 mgand 2.5 mg testosterone.
 7. The pharmaceutical composition of claim 1,wherein the composition comprises between 0.3 mg and 2.5 mgtestosterone.
 8. The pharmaceutical composition of claim 1, wherein the5-HT1A agonist is buspirone.
 9. The pharmaceutical composition of claim1 which is a sublingual or buccal-mucosal formulation.
 10. Thepharmaceutical composition of claim 9 which is a sublingual formulation.11. The pharmaceutical composition of claim 1, wherein said delayedrelease is effected by surrounding the 5-HT1A agonist by a coating.